P326: PROGNOSTIC UTILITY OF NON-HOMOLOGOUS END JOINING DNA REPAIR PATHWAY GENES IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: S. KUMARI, J. SINGH, M. Arora, S. Bakhshi, J. K. Palanichamy, A. Sharma, P. Tanwar, A. R. Singh, I. Qamar, A. Chopra
Journal: HemaSphere (2022)

Background: T-ALL is a molecularly heterogeneous malignancy characterized by transformation and differentiation blockage at different stages of T cell development. Efficient DNA repair has shown to enable leukemic cells to survive the damaging effects of therapeutics, therefore, understanding of DNA repair alterations in leukemia may provide novel druggable targets and prognostic biomarkers. Notably, it is important to determine that whether the variable ability of T cell to repair DNA damage also translates into the corresponding molecular profiles of T-ALL. Several components of different DNA repair pathways have been recently identified to play critical role in ALL pathophysiology and drug resistance. However, the clinical significance of major DNA double strand break repair pathway Non-Homologous End Joining (NHEJ) in T cell acute lymphoblastic leukemia remains to be studied in detail. Aims: This study aims to assess the importance of DNA damage response pathways in T-cell acute lymphoblastic leukemia cancer (ALL). Methods: We assessed the gene expression pattern of 21 genes involved in NHEJ pathwayincluding six core genes, accessory genes and other regulators such as MRE complex genes in 207 T-ALL patients. In order to determine the changes in expression pattern of NHEJ genes during the course of T-ALL, gene expression was assessed at different time points, including clinical sample at diagnosis, minimal residual diseaseand at relapse. Real time PCR was used to assess the expression of these genes. We further determined the association of NHEJ pathway gene expression with clinical and molecular features. Results: We observed higher expression of TOX, WRN, NHEJ1, APLF, TDP2 and reduced expression of XRCC4, POLL, PRKDC, APTX, PNKP, XRCC5, DCLRC1C, MRE11, XRCC6, NBN in diagnostic T-ALL samples compared to normal bone marrow. Further, PRKDC, RAD50, and XRCC6 displayed lesser expression in prednisolone resistant group compared to sensitive group. At minimal residual disease, XRCC4, POLL, WRN, POLM, APTX, PNKP, XRCC5, DCLRC1C, XRCC6, NBN, TDP1 exhibited higher expression and TOX, LIG4, MRE11 exhibited reduced expression compared to diagnostic samples. XRCC4, PRKDC, NHEJ1, PNKP, XRCC5, DCLRC1C, MRE11, XRCC6, NBN and TDP1 exhibited higher expression in relapse samples compared to diagnostic samples. The clinical significance of expression of NHEJ genes was explored in detail. Low expression of XRCC4, PRKDC, RAD50, XRCC5, XRCC6 and TDP1 gene was associated with immature immunophenotype (IPT) as compared to cortical and mature IPT.Patients with ETP-ALL IPT more frequently had lesser expression of XRCC4, PRKDC, RAD50, LIG4, APTX, MRE11, XRCC6andgene compared to other IPT groups. In diagnostic samples, higher XRCC4 expression was associated with better overall survival (OS) and even free survival (EFS). Additionally, low WRN expression was associated with poor EFS and relapse free survival (RFS). Interestingly, high DCLRC1C expression was associated with favorable OS, EFS and RFS. Summary/Conclusion: We observed a distinct expression profile of NHEJ genes among molecularly heterogeneous groups of T-ALL patient’spossibly explaining different extent of DNA repair among patient with different immunological groups and in response to therapy. Interestingly, this depicted a clear change in the DNA repair responses in the leukemia patients before and post chemotherapy. Gene expression emerged as the predictor of OS, EFS and RFS in T-ALL patientsthat might be helpful in the improvement of the treatment outcome in T-ALL therapy